The long-term objective of this application is to characterize the genetic basis for ischemic stroke susceptibility in order to develop more effective prevention and treatment strategies. Current evidence suggests that the genes encoding the thrombomodulin - protein C and fibrinolysis systems are promising candidate stroke susceptibility genes because of their pivotal importance in thrombosis regulation and response to inflammation. We postulate that: 1) novel genetic variants in the thrombomodulin, endothelial protein C receptor, and plasminogen activator inhibitor-1 genes predispose to the development of stroke, particularly infection-associated stroke and 2) endothelial protein C receptor polymorphisms are associated with large vessel stroke, while thrombomodulin polymorphisms are associated with lacunar (small vessel) stroke. To obtain a sample size adequate to test these hypotheses, we propose a population-based case-control study of ischemic stroke (1,033 cases and 1,064 controls) among young African-American and Caucasian men and women. To complement an existing sample of female cases and controls, male cases (n=600) will be recruited using a network of 59 hospitals in the Baltimore-Washington area. Age, gender, and racematched controls (n=600) will be recruited by random digit dialing. A neurologist panel will perform stroke phenotyping. Historical risk factor data and blood samples for genetic studies will be obtained at a face-to-face interview. A comprehensive molecular analysis of the coding, promotor, and intronic regions of the three candidate genes will be performed to determine if sequence variation in these loci is associated with stroke. In addition to analyses of individual polymorphisms, intragenic haplotypes will be constructed and common haplotypes tested for association with stroke. Population substructure analysis will be used to identify and account for population stratification bias in the analyses. The proposed study will complement other association studies of older stroke patients and will be a continuing resource for understanding the genetic basis of stroke risk.